Electrical substance clearance from the brain for treatment of alzheimer&#39;s disease

ABSTRACT

Apparatus is provided that includes a parenchymal electrode, configured to be implanted in brain parenchyma of a subject identified as at risk of or suffering from Alzheimer&#39;s disease; and a ventricular electrode, configured to be implanted in a ventricular system of a brain of the subject. Control circuitry is configured to drive the parenchymal and the ventricular electrodes to clear a substance from the brain parenchyma into the ventricular system. Other embodiments are also described.

FIELD OF THE APPLICATION

The present invention relates generally to treatment and prevention ofAlzheimer's disease, and specifically to electrical techniques fortreating, preventing, or slowing the progression of Alzheimer's disease.

BACKGROUND OF THE APPLICATION

Alzheimer's disease is a chronic neurodegenerative disease that causesdementia. Accumulation of substances such as amyloid beta and/or tauprotein in the brain is widely believed to contribute to the developmentof Alzheimer's disease.

US Patent Application Publication 2014/0324128 to Gross, which isassigned to the assignee of the present application and is incorporatedherein by reference, describes apparatus for driving fluid between firstand second anatomical sites of a subject. The apparatus comprises (1) afirst electrode, configured to be coupled to the first anatomical siteof the subject; (2) a second electrode, configured to be coupled to thesecond anatomical site of the subject; and (3) a control unit,configured to (i) detect a pressure difference between the first andsecond anatomical sites, and (ii) in response to the detected pressuredifference, drive fluid between the first and second anatomical sites byapplying a treatment voltage between the first and second electrodes.Other embodiments are also described.

SUMMARY OF THE APPLICATION

Some embodiments of the present invention provide techniques fortreating Alzheimer's disease. in some applications of the presentinvention, a parenchymal electrode is implanted in parenchyma of thebrain, and a ventricular electrode is implanted in a ventricular systemof the brain. Control circuitry is activated to drive the parenchymaland the ventricular electrodes to clear a substance, such as amyloidbeta and/or tau protein, from the brain parenchyma into the ventricularsystem.

There is therefore provided, in accordance with an application of thepresent invention, apparatus including:

a parenchymal electrode, configured to be implanted in brain parenchymaof a subject identified as at risk of or suffering from Alzheimer'sdisease;

a ventricular electrode, configured to be implanted in a ventricularsystem of a brain of the subject; and

control circuitry, configured to drive the parenchymal and theventricular electrodes to clear a substance from the brain parenchymainto the ventricular system.

For some applications, the substance includes amyloid beta, and thecontrol circuitry is configured to drive the parenchymal and theventricular electrodes to clear the amyloid beta from the brainparenchyma into the ventricular system. For some applications, thesubstance includes metal ions, and the control circuitry configured todrive the parenchymal and the ventricular electrodes to clear the metalions from the brain parenchyma into the ventricular system. For someapplications, the substance includes tau protein, and the controlcircuitry is configured to drive the parenchymal and the ventricularelectrodes to clear the tau protein from the brain parenchyma into theventricular system.

For some applications, the parenchymal electrode is configured to beimplanted in white matter of the brain.

For some applications, the control circuitry is configured to configurethe parenchymal electrode to be an anode, and the ventricular electrodeto be a cathode. For some applications, the control circuitry isconfigured to configure the parenchymal electrode to be a cathode, andthe ventricular electrode to be an anode.

For some applications, the control circuitry is configured toadditionally apply deep brain stimulation using the parenchymalelectrode.

For some applications, the control circuitry is configured to beimplanted under skin of the subject.

For some applications, the control circuitry is configured to drive theparenchymal and the ventricular electrodes to clear the substance byapplying a non-excitatory current between the parenchymal and theventricular electrodes.

For some applications, the control circuitry is configured to drive theparenchymal and the ventricular electrodes to clear the substance byapplying direct current between the parenchymal and the ventricularelectrodes. For some applications, the control circuitry is configuredto apply the direct current with an average amplitude of between 1 and 5mA. For some applications, the control circuitry is configured to applythe direct current with an average amplitude of less than 1.2 V.

For some applications, the control circuitry is configured to apply thedirect current as a series of pulses. For some applications, the controlcircuitry is configured to apply the direct current as the series ofpulses having an average pulse duration of between 100 milliseconds and300 seconds. For some applications, the control circuitry is configuredto apply the direct current as the series of pulses with a duty cycle ofbetween 1% and 50%.

For some applications, the control unit is configured to:

drive the parenchymal and the ventricular electrodes to clear thesubstance by applying a voltage between the parenchymal and theventricular electrodes during each of the pulses,

while applying the voltage, measure a current resulting from applicationof the voltage during the pulse, and

terminate the pulse upon the measured current falling below a thresholdvalue.

For some applications, the threshold value is based.

on an initial current magnitude measured upon commencement of the pulse.

There is further provided, in accordance with an application. of thepresent invention, a method including:

implanting a parenchymal electrode in brain parenchyma of a subjectidentified as at risk of or suffering from Alzheimer's disease;

implanting a ventricular electrode in a ventricular system of a brain ofthe subject; and

activating control circuitry to drive the parenchymal and theventricular electrodes to clear a substance from the brain parenchymainto the ventricular system.

For some applications, the substance includes amyloid beta, andactivating the control circuitry includes activating the controlcircuitry to drive the parenchymal and the ventricular electrodes toclear the amyloid beta from the brain parenchyma into the ventricularsystem. For some applications, the substance includes metal ions, andactivating the control circuitry includes activating the controlcircuitry to drive the parenchymal and the ventricular electrodes toclear the metal ions from the brain parenchyma into the ventricularsystem. For some applications, the substance includes tau protein, andactivating the control circuitry includes activating the controlcircuitry to drive the parenchymal and the ventricular electrodes toclear the tau protein from the brain parenchyma into the ventricularsystem.

For some applications, implanting the parenchymal electrode in the brainparenchyma includes implanting the parenchymal electrode in white matterof the brain.

For some applications, activating the control circuitry includesactivating the control circuitry to configure the parenchymal electrodeto be an anode, and the ventricular electrode to be a cathode. For someapplications, activating the control circuitry includes activating thecontrol circuitry to configure the parenchymal electrode to be acathode, and the ventricular electrode to be an anode.

For some applications, the method further includes applying deep brainstimulation using the parenchymal electrode.

For some applications, the method further includes implanting thecontrol circuitry under skin of the subject.

For some applications, activating the control circuitry to drive theparenchymal and the ventricular electrodes includes activating thecontrol circuitry to drive the parenchymal and the ventricularelectrodes to clear the substance by applying a non-excitatory currentbetween the parenchymal and the ventricular electrodes.

For some applications, activating the control circuitry to drive theparenchymal and the ventricular electrodes includes activating thecontrol circuitry to drive the parenchymal and the ventricularelectrodes to clear the substance by applying direct current between theparenchymal and. the ventricular electrodes. For some applications,activating the control circuitry to apply the direct current includesactivating the control circuitry to apply the direct current. with anaverage amplitude of between 1 and 5 mA. For some applications,activating the control circuitry to apply the direct current includesactivating the control circuitry to apply the direct current with anaverage amplitude of less than 1.2 V.

For some applications, activating the control circuitry to apply thedirect current includes activating the control circuitry to apply thedirect current as a series of pulses, For some applicatons, activatingthe control circuitry to apply the direct current as the series ofpulses includes activating the control circuitry to apply the directcurrent as the series of pulses having an average pulse duration ofbetween 100 milliseconds and 300 seconds. For some applications,activating the control circuitry to apply the direct current as theseries of pulses includes activating the control circuitry to apply thedirect current as the series of pulses with a duty cycle of between 1%and 50%.

For some applications, activating the control circuitry to drive theparenchymal and the ventricular electrodes includes activating thecontrol unit to:

drive the parenchymal and the ventricular electrodes to clear thesubstance by applying a voltage between the parenchymal and theventricular electrodes during each of the pulses,

while applying the voltage, measure a current resulting from applicationof the voltage during the pulse, and

terminate the pulse upon the measured current falling below a thresholdvalue.

For some applications, the threshold value is based on an initialcurrent magnitude measured upon commencement of the pulse.

For some applications, implanting the parenchymal and the ventricularelectrodes includes implanting the parenchymal and the ventricularelectrodes such that an area of build-up of the substance is between theparenchymal and the ventricular electrodes. For some applications,implanting the parenchymal and the ventricular electrodes includesidentifying the area of build-up of substance in the brain parenchymabefore implanting the parenchymal and the ventricular electrodes. Forsome applications, identifying the area of build-up includes performingimaging of the brain. For some applications, performing the imagingincludes performing functional MRI (fMRI) imaging of the brain.

For some applications, implanting the parenchymal electrode includesimplanting the parenchymal electrode such that an area of build-up ofthe substance is between the parenchymal electrode and an area of theventricular system nearest the area of build-up. For some applications,implanting the parenchymal electrode includes identifying the area ofbuild-up of the substance in the brain parenchyma before implanting theparenchymal electrode. For some applications, identifying the area ofbuild-up includes performing imaging of the brain. For someapplications, performing the imaging includes performing functional MRI(fMRI) imaging of the brain.

The present invention will be more fully understood from the followingdetailed. description of embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-C are schematic illustrations of a system for treatingAlzheimer's disease, in accordance with respective applications of thepresent invention; and

FIGS. 2A-B are schematic illustrations of cross-sections of a rat brainshowing results of an animal experiment performed in accordance with anapplication of the present invention.

DETAILED DESCRIPTION OF APPLICATIONS

FIGS. 1A-C are schematic illustrations of a system 20 for treatingAlzheimer's disease, in accordance with respective applications of thepresent invention. System 20 comprises parenchymal and ventricularelectrodes 30 and 32, and control circuitry 34, which is electricallycoupled to parenchymal and ventricular electrodes 30 and 32, typicallyby parenchymal and ventricular electrode leads 36 and 38, respectively.

In some applications of the present invention, parenchymal electrode 30is implanted in parenchyma 50 of a brain 52 of a subject identified asat risk of or suffering from Alzheimer's disease, e.g., using techniquessimilar to those for implantation of electrodes for deep brainstimulation. Ventricular electrode 32 is implanted in a ventricularsystem 54 of brain 52. For example, ventricular electrode 32 may beimplanted. using techniques known for implanting hydrocephalus shunts,mutatis mutandis. As used in the present application, including in theclaims, ventricular system 54 includes and is limited to lateralventricles (left and right lateral ventricles 55A and 55B), a thirdventricle 56, a fourth ventricle 57, a cerebral aqueduct,interventricular foramina, a median aperture, and left and right lateralapertures.

Control circuitry 34 is activated to drive parenchymal and ventricularelectrodes 30 and 32 to clear a substance from brain parenchyma 50 intoventricular system 54. For some applications, the substance comprisesamyloid beta, metal ions, a tau protein, and/or a waste substance. Asused in the present application, including in the claims, clearing asubstance from the brain parenchyma is to be understood as includingclearing a portion of the substance, without clearing all of thesubstance. Typically, in order to clear the substance, control circuitry34 applies a voltage between parenchymal and ventricular electrodes 30and 32.

Typically, a healthcare worker, such as a physician, activates controlcircuitry 34 to provide the functions described herein. Activating thecontrol unit may include configuring parameters and/or functions of thecontrol circuitry (such as using a separate programmer or externalcontroller), or activating the control unit to perform functionspre-programmed in the control circuitry. Control circuitry 34 typicallycomprises appropriate memory, processor(s), and hardware runningsoftware that is configured to provide the functionality of controlcircuitry described herein.

Current may flow generally through tissue that is located. betweenparenchymal and. ventricular electrodes 30 and 32. Alternatively oradditionally, at least a portion of the current may flow between (a)parenchymal electrode 30 and (b) an area of the ventricular system 54nearest parenchymal electrode 30. The inventors have appreciated thatbecause of the low electrical resistance of cerebrospinal fluid (CSF))in ventricular system 54, the ventricles are to some extent a singleentity electrically. Therefore, a large portion of the current flows tothe nearest portion of ventricular system 54, even if ventricularelectrode 32 is implanted in a ventricle remote from parenchymalelectrode 30. For example, as shown in FIG. 1B, if a parenchymalelectrode 30A. is implanted in a right hemisphere of brain 52, most ofthe current may flow between. parenchymal electrode 30A and an area 58of right ventricle 55B nearest parenchymal electrode 30A, even thoughventricular electrode 32 is implanted in left ventricle 55A.

For some applications, the voltage applied between the electrodes mayclear the substance electrophoretically, because of a positive ornegative charged interface between the surface of the particles of thesubstance and the surrounding brain tissue fluids. For theseapplications, the voltage applied between the electrodes causes apotential difference between brain parenchyma 50 and ventricular system54, which causes movement of the substance from brain parenchyma 50 toventricular system 54. Alternatively or additionally, for someapplications, the voltage applied between the electrodes may clear thesubstance electroosmotically, because of a positive or negative chargeof fluid in the parenchyma. For these applications, the voltage appliedbetween the electrodes causes a potential difference between brainparenchyma 50 and ventricular system 54, which causes increased flowfrom brain parenchyma 50 to ventricular system 54, and thus increasedtransport of the substance from parenchyma 50 to ventricular system 54.

For some applications, system 20 comprises a plurality of parenchymalelectrodes 30 and/or a plurality of ventricular electrodes 32.Parenchymal electrodes 30 may be implanted in one or both hemispheres ofbrain 52, and/or at one or more than one location in each of thehemispheres. For some applications, such as shown in FIGS. 1A-C, system20 comprises a plurality of parenchymal electrodes 30 and exactly oneventricular electrode 32. For example, the single ventricular electrode32 may be implanted in one of lateral ventricles 55 or third ventricle56, which, as discussed above, are to a large degree in good electricalconnectivity with the other ventricles. For other applications(configuration not shown), system 20 comprises (a) exactly twoventricular electrodes 32, which are implanted in left and right lateralventricles 55A and 55B, respectively, or (b) exactly three ventricularelectrodes 32, which are implanted in left and right lateral ventricles55A and 55B and third ventricle 56, respectively.

For applications in which system 20 comprises a plurality of parenchymalelectrodes 30 and/or a plurality of ventricular electrodes 32, system 20typically comprises a corresponding plurality of parenchymal electrodeleads 36 and/or a corresponding plurality of ventricular electrode leads38. Each of the leads may comprise separate electrical insulation,and/or a portion of the leads may be joined and share common electricalinsulation, as shown in FIGS. 1A-C for parenchymal electrode leads 36.Control circuitry 34 may be activated to independently drive parenchymalelectrodes 30, e.g., using separately circuitry. Alternatively, one ormore of parenchymal electrodes 30 may be shorted to one another, suchthat the control circuitry drives the shorted electrodes together.Control circuitry 34 may be activated to drive parenchymal electrodes 30simultaneously or at different times.

For some applications, brain parenchyma 50 in which parenchymalelectrode 30 is implanted comprises white matter of the brain.

As used in the present application, including the claims, “treating”includes both treating a subject already diagnosed with Alzheimer'sdisease (such as by delaying, slowing, or reversing progression. of thedisease, e.g., in a patient diagnosed at an early stage), as well aspreventing the development of Alzheimer's disease in a subject notdiagnosed with the disease and/or asymptomatic for the disease. Forexample, the techniques described herein may be used to prevent or delaythe development of Alzheimer's disease in responsive to detection of anabnormal level of amyloid beta, such as using a blood test or a spinaltap.

For some applications, control circuitry 34 is configured to beimplanted subcutaneously, such under skin of the skull of the subject ifthe housing containing the control circuitry is small, or elsewhere inthe subject's body, such as in the upper chest, if the housing of thecontrol circuitry is larger (e.g., includes batteries), with leadsthrough the neck, or optionally in the head. For these applications,control circuitry 34 is typically driven by an external controller thatis in wireless or wired communication with control circuitry 34. Forsome applications, the external controller is mounted on a bed of thesubject (e.g., disposed within a mattress), and is configured toactivate control circuitry 34 only at night, and/or only when thesubject is sleeping. Such nighttime activation may to some degree mimicthe natural timing of clearance of the substance (e.g., amyloid beta ortau protein) during sleep. For other applications, control circuitryconfigured to be disposed externally to the subject.

For some applications, control circuitry 34 is activated to driveparenchymal and ventricular electrodes 30 and 32 to clear the substanceby applying a non-excitatory current between parenchymal and ventricularelectrodes 30 and 32, i.e., the current does not cause propagation ofaction potentials. Thus, in these applications, control circuitry 34 isactivated to set parameters of the current such that the current doesnot affect, or only minimally affects, neuronal activity. Alternatively,the applied current does excite brain tissue, such as to a small extent.

For some applications, control circuitry 34 is activated to driveparenchymal and ventricular electrodes and 32 to clear the substance byapplying direct current (DC) between parenchymal and ventricularelectrodes 30 and 32. As used in the present application, including inthe claims, direct current means a current having a constant polarity;the amplitude of the direct current may or may not vary over time, andmay sometimes be zero.

For some applications, control circuitry 34 is activated. to apply thedirect current with an average amplitude of at least 1 mA, no more than5 mA, and/or between 1 and 5 mA. Alternatively or additionally, for someapplications, control circuitry 34 is activated to apply the directcurrent with an average amplitude of less than 1.2 V (such an amplitudemay avoid electrolysis in the vicinity of one or both of theelectrodes).

For some applicatons, control circuitry 34 is activated to configureparenchymal electrode 30 to be an anode, and ventricular electrode 32 tobe a cathode. Alternatively, control circuitry 34 is activated toconfigure parenchymal electrode 30 to be a cathode, and ventricularelectrode 32 to be an anode. For applications in which. the voltageapplied between the electrodes clears the substance electrophoretically,the selected polarity of the electrodes typically depends on whether thesubstance has a positive or negative effective charge. Similarly, forapplications in which the voltage applied between the electrodes clearsthe substance electroosmotically, the selected polarity of theelectrodes typically depends on whether the fluid has a positive ornegative effective charge.

For some applications, control circuitry 34 is activated to apply thedirect current as a series of pulses. For some applications, the seriesof pulses has an average pulse duration of at least 10 milliseconds, nomore than 300 seconds, and/or between 10 milliseconds and 300 seconds,such as: (a) at least 10 milliseconds, no more than 100 milliseconds,and/or between 10 and 100 milliseconds, (b) at least 100 milliseconds,no more than 300 seconds (e.g., no more than 500 milliseconds), and/orbetween 100 and 300 seconds (e.g., between 100 and 500 milliseconds),(c) at least 500 milliseconds, no more than 5 seconds, and/or between500 milliseconds and 5 seconds, (d) at least 5 seconds, no more than 10seconds, and/or between 5 and 10 seconds, or (e) at least 10 seconds, nomore than 100 seconds, and/or between 10 and 100 seconds. For someapplications, the pulses are applied at a frequency of at least 0.001Hz, no more than 1 kHz, and/or between 0.001 and 1 kHz, such as: (a) atleast 100 Hz, no more than 1 kHz, and/or between 100 Hz and 1 kHz, (b)at least 20 Hz, no more than 100 Hz, and/or between 20 and 100 Hz, or(c) at least 1 Hz, no more than 10 Hz, and/or between 1 and 10 Hz.Alternatively or additionally, for some applications, the series ofpulses has a duty cycle of at least 1%, no more than 50%, and/or between1% and 50%, such as: (a) at least 1%, no more than 5%, and/or between 1%and 5%, (b) at least 5%, no more than 10%, and/or between 5% and 10%,(c) at least 10%, no more than 25%, and/or between 10% and 25%, or (d)at least 25%, no more than 50%, and/or between 25% and 50%. Typically,but not necessarily, the duty cycle is no more than 90%, because a givenlevel of applied voltage produces higher current in the tissue if thecapacitance in the tissue is allowed to discharge between pulses.

For some of these applications in which control circuitry 34 applies avoltage between parenchymal and ventricular electrodes 30 and 32 in aseries of DC pulses, the resulting current decays because of the effectsof tissue electrolytes. The current may decay by about two-thirds of itsinitial magnitude within tens of milliseconds after commencement ofapplication of each pulse. In order to overcome this capacitance effect,control circuitry 34 is activated to apply the voltage intermittently,in order to provide time periods between pulses during which thecapacitance discharges.

For some applications, control circuitry 34 is activated to apply thevoltage intermittently with a preprogrammed frequency and/or duty cycle.These parameters may be (a) applicable to all patients or a subgroup ofpatients, (b) set during a calibration procedure upon implantation ofthe electrodes, or (c) set based on a geometry of placement ofparenchymal and/or ventricular electrodes 30 and/or 32. Alternatively,control circuitry 34 is configured to set these parameters in real timeby sensing the current resulting from the applied voltage.

For some applications, control circuitry 34 is activated to measure thecurrent resulting from the applied voltage during each of the appliedpulses, and to terminate each of the applied pulses when the magnitudeof the measured current falls below a threshold value. For example, thethreshold value may be a preprogrammed constant, or may be based on(e.g., a percentage of) the initial current magnitude measured uponcommencement of the respective pulse. Control circuitry 34 waits duringa discharge period before applying the next pulse.

For some applications, control circuitry 34 is activated to apply,between parenchymal and ventricular electrodes 30 and 32, alternatingcurrent (AC) in:

-   -   a primary subset of the pulses at a primary polarity selected to        electrophoretically and/or electroosmotically clear the        substance, at a primary voltage and with a primary average pulse        duration, and    -   a secondary subset of the pulses at a secondary polarity        opposite the primary polarity, at a secondary voltage less than        the primary voltage, and with a secondary average pulse duration        greater than the primary average pulse duration.

Because of the lower secondary voltage, the secondary subset of thepulses to a large extent does not reverse the clearance of the substanceachieved during application of the primary subset of the pulses. Thistechnique may also help avoid electrolysis in the vicinity of one orboth of the electrodes, even the primary voltage is higher than athreshold DC voltage (e.g., 1.2 V) that might otherwise causeelectrolysis.

For some applications, such as illustrated in FIG. 1C, parenchymal andventricular electrodes 30 and 32 are implanted. such that one or moreareas of build-up 64 of the substance in brain parenchyma 50 is betweenthe electrodes, rather than implanting parenchymal electrode 30 withinthe area of build-up. For example, the area(s) of build-up may includeamyloid plaque and/or tau protein-related nerve tissue tangles. To thisend, typically the area of build-up is first identified, for example byperforming imaging of brain 52, such as MRI (e.g., functional MRI(fMRI)) or PET imaging of brain 52. As mentioned above, a plurality ofparenchymal electrodes 30 and/or a plurality of ventricular electrodes32 may be implanted, such as if there is more than one area of build-up64 of the substance.

For some applications, also such as illustrated in FIG. 1C, the one ormore parenchymal electrode are implanted such that the one or more areasof build-up 64 are between parenchymal electrode 30A and respectiveareas 80 of ventricular system 54 nearest areas of build-up 64.Ventricular electrode 32 may or may not be implanted near areas 80. Forapplications in which ventricular electrode 32 is not implanted nearareas 80, the substance of area of build-up 64 may still be driven intonearest areas 80 of ventricular system 54, because nearest areas 80 arein fluid communication with ventricular electrode 32 via CSF ofventricular system 54, as discussed above. As mentioned above, aplurality of parenchymal electrodes 30 and/or a plurality of ventricularelectrodes 32 may be implanted, such as if there is more than one areaof build-up 64 of the substance, or in general in order to provide goodclearance of the substance.

For some applications, parenchymal electrode 30 is further used forapplying deep brain stimulation, as is known in the art. For example,the deep brain stimulation may be applied when the electrodes are notbeing driven to drive the substance into the ventricular system. As isknown in the art, the deep brain stimulation may be applied to reducetremor and block involuntary movements in patients with motiondisorders, such as Parkinson's disease, or to treat epilepsy, clusterheadaches, Tourette syndrome, chronic pain, or major depression. Theimplantation location of parenchymal electrode 30 may he selected to beappropriate for the treatment of a particular condition, as well as forclearing the substance.

For some applications, control circuitry 34 is activated to driveparenchymal and ventricular electrodes 30 and 32 in sessions, each ofwhich has a duration of several seconds or several minutes, orcontinuously for longer Periods (e.g., 30 minutes). For someapplications, the electrodes are not driven for a period that is atleast an hour. Optionally, control circuitry 34 is activated to drivethe electrodes only when the subject is sleeping, such as to inhibit anysensations that may be associated with the driving. For someapplications, power for activating and/or charging control circuitry 34is transmitted from a wireless energy transmitter in a device applied tothe head, such as a hat, or from a wireless energy transmitter in,under, or above a mattress, such as described hereinabove. For someapplications, control circuitry 34 is activated to drive the electrodesaccording to a pre-selected schedule, such as a duty cycle, such as fora few hours per day. For example, control circuitry 34 may be configuredto be controlled and/or powered by an extracorporeal control circuitry,such as a control circuitry comprising a wireless transmitter, disposedin and/or in the vicinity of the subject's bed. For some applications,one or more rest periods during which the control circuitry does notdrive the electrodes are provided in the pre-selected schedule.

For any of the applications described herein, ventricular electrode 32may be implanted in one of the following sites, rather than inventricular system 54:

-   -   a central canal of the spinal cord (which is in fluid        communication with ventricular system 54);    -   a superior sagittal sinus (which is in fluid communication with        ventricular system 54 because CSF drains into the superior        sagittal sinus from ventricular system 54); or    -   a subarachnoid space (which is in fluid communication with        ventricular system 54 because CSF drains into cisterns of the        subarachnoid space via foramina of ventricular system 54).

For any of the applications described herein, parenchymal electrode 30may be implanted in a superior sagittal sinus, rather than in brainparenchyma 50 (typically, in these applications, ventricular electrode32 is implanted in ventricular system 54).

For some applications, parenchymal and ventricular electrodes 30 and 32are implanted in brain parenchyma 50 and ventricular system 54,respectively, and third and fourth electrodes are implanted in thesuperior sagittal sinus and ventricular system 54, respectively. Controlcircuitry 34 is activated to apply a first voltage between parenchymaland. ventricular electrodes 30 and 32, and a second voltage between thethird and the fourth electrodes.

Alternatively, for some applications, parenchymal and ventricularelectrodes 30 and 32 are implanted in brain parenchyma 50 andventricular system 54, respectively, and a third electrode is implantedin the superior sagittal sinus. Control circuitry 34 is activated toapply a first voltage between parenchymal and ventricular electrodes 30and 32, and a second voltage between ventricular electrode 32 and thethird electrode. For some of these applications, control circuitry 34 isactivated to set:

-   -   a first polarity of ventricular electrode 32 when applying the        first voltage between parenchymal and ventricular electrodes 30        and 32, so as to drive the substance from brain parenchyma 50        into ventricular system 54, and    -   a second polarity of ventricular electrode 32, opposite the        first polarity, when applying the second voltage between        ventricular electrode 32 and the third electrode, so as to drive        the substance from ventricular system 54 into the superior        sagittal sinus.

Reference is now made to FIGS. 2A-B, which are schematic illustrationsof cross-sections of a rat brain showing results of an animal experimentperformed in accordance with an application of the present invention. Arat was anesthetized, a first electrode 130 (a piece of Pt-Ir wiresoldered to a miniature connector) was inserted through a hole into thesagittal sinus, and a second electrode 132 (a pieces of Pt-Ir wiresoldered to a small electronic connector) was inserted through a hole indura mater into the right lateral ventricle.

As shown in FIG. 2A, bromephenol blue dye was stereotaxically deliveredinto both hemispheres of the rat brain at designated coordinates 120 and122. By using the left hemisphere as a diffusion control, thisexperimental setup allowed pairwise comparisons within the same animal,thereby ruling out any other effects that might effect a directedmigration of the dye in the brain.

Control circuitry was activated to apply a constant-polarity (DC)current to only the right hemisphere, between first and secondelectrodes 130 and 132, configuring first electrode 130 as a cathode andsecond electrode 132 as an anode, because bromephenol blue dye compriseseffectively anionic (negatively-charged) molecules. The current wasapplied by repeatedly alternating between two modes: (a) a first mode,in which the current was applied continuously for 5 minutes at amagnitude of 1-2 mA, and (b) a second mode, in which the current wasapplied in 10-ms-duration pulses, one pulse per second (i.e., a pulsefrequency of 1 Hz), at a magnitude of 1-2 mA.

FIG. 2B shows the displacement of the bromephenol blue dye afterapplication of the current to the right hemisphere. As can be seen, thebromephenol blue dye in the left hemisphere experienced minimaldispersion and no directed displacement. In contrast, in the righthemisphere, the applied current moved the bromephenol blue dye towardthe lateral ventricle. The dye moved with the average velocity of0.28+/−0.006 mm/min, which was more than 14 times greater than theobserved diffusion rate in the left hemisphere. In the right hemisphere,the linear displacement of the dye profile center was about 1.9±0.08 mm,while the front of the dye profile reached a maximum distance of about2.81±0.07 mm from the center of the injection point.

The results of this experiment demonstrated that molecules of dye can bemoved within brain tissue by applying a DC current using two electrodesimplanted in the brain, and that in such a setup, a natural migrationpath is toward the ventricles. The inventors believe that application ofthe current between the electrodes may have moved the dyeelectrophoretically. The inventors also believe that implantation of thefirst electrode directly in brain parenchyma, rather than in thesagittal sinus, may provide even better current-driven movement ofmolecules, because the resistance of the parenchyma-sinus interface wascalculated as more than two-fold higher than the resistance measuredwithin the parenchyma, based on data collected during the experiment.

The scope of the present invention includes embodiments described in thefollowing applications, which are assigned to the assignee of thepresent application and are incorporated herein by reference. in anembodiment, techniques and apparatus described in one or more of thefollowing applications are combined with techniques and apparatusdescribed herein:

-   -   U.S. application Ser. No. 13/872,794, filed Apr. 20, 2013, which        published as US Patent Application Publication 2014/0324128; and

U.S. application Ser. No. 14/794,739, filed Jul. 8, 2015.

It will be appreciated by persons skilled in. the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed. hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description.

1. Apparatus comprising: a parenchymal electrode, configured to beimplanted in brain parenchyma of a subject identified as at risk of orsuffering from Alzheimer's disease; a ventricular electrode, configuredto be implanted in a ventricular system of a brain of the subject; andcontrol circuitry, configured to drive the parenchymal and theventricular electrodes to clear a substance from the brain parenchymainto the ventricular system la applying direct current between theparenchymal and the ventricular electrodes with an average amplitude ofno more than 5 mA, the substance comprising one or more substancesselected from the group of substances consisting of: amyloid beta, tauprotein, and metal ions.
 2. The apparatus according to claim 1, whereinthe substance includes amyloid beta, and wherein the control circuitryis configured to drive the parenchymal and the ventricular electrodes toclear the amyloid beta from the brain parenchyma into the ventricularsystem.
 3. (canceled)
 4. The apparatus according to claim 1, wherein thesubstance includes tau protein, and wherein the control circuitry isconfigured to drive the parenchymal and the ventricular electrodes toclear the tau protein from the brain parenchyma into the ventricularsystem. 5-6. (canceled)
 7. The apparatus according to claim 1, whereinthe control circuitry is configured to configure the parenchymalelectrode to be a cathode, and the ventricular electrode to be an anode.8-9. (canceled)
 10. The apparatus according to claim 1, wherein thecontrol circuitry is configured to drive the parenchymal and theventricular electrodes to clear the substance by applying the directcurrent as non-excitatory current between the parenchymal and theventricular electrodes. 11-13. (canceled)
 14. The apparatus according toclaim 1, wherein the control circuitry is configured to apply the directcurrent as a series of pulses.
 15. The apparatus according to claim 14,wherein the control circuitry is configured to apply the direct currentas the series of pulses having an average pulse duration of between 100milliseconds and 300 seconds.
 16. (canceled)
 17. The apparatus accordingto claim 14, wherein the control unit is configured to: drive theparenchymal and the ventricular electrodes to clear the substance byapplying a voltage between the parenchymal and the ventricularelectrodes during each of the pulses, measure a current resulting fromapplication of voltage during each of the pulses, and terminate thepulse upon the measured current falling below a threshold value. 18.(canceled)
 19. A method comprising: implanting a parenchymal electrodein brain parenchyma of a subject identified as at risk of or sufferingfrom Alzheimer's disease; implanting a ventricular electrode in aventricular system of a brain of the subject; and activating controlcircuitry to drive the parenchymal and the ventricular electrodes toclear a substance from the brain parenchyma into the ventricular systemla applying direct current between the parenchymal and the ventricularelectrodes with an average amplitude of no more than 5 mA, the substancecomprising one or more substances selected from the group of substancesconsisting of: amyloid beta, tau protein, and metal ions.
 20. The methodaccording to claim 19, wherein the substance includes amyloid beta, andwherein activating the control circuitry comprises activating thecontrol circuitry to drive the parenchymal and the ventricularelectrodes to clear the amyloid beta from the brain parenchyma into theventricular system.
 21. (canceled)
 22. The method according to claim 19,wherein the substance includes tau protein, and wherein activating thecontrol circuitry comprises activating the control circuitry to drivethe parenchymal and the ventricular electrodes to clear the tau proteinfrom the brain parenchyma into the ventricular system. 23-24. (canceled)25. The method according to claim 19, wherein activating the controlcircuitry comprises activating the control circuitry to configure theparenchymal electrode to be a cathode, and the ventricular electrode tobe an anode. 26-27. (canceled)
 28. The method according to claim 19,wherein activating the control circuitry to drive the parenchymal andthe ventricular electrodes comprises activating the control circuitry todrive the parenchymal and the ventricular electrodes to clear thesubstance by applying the direct current as non-excitatory currentbetween the parenchymal and the ventricular electrodes. 29-31.(canceled)
 32. The method according to claim 19, wherein activating thecontrol circuitry to apply the direct current comprises activating thecontrol circuitry to apply the direct current as a series of pulses. 33.The method according to claim 32, wherein activating the controlcircuitry to apply the direct current as the series of pulses comprisesactivating the control circuitry to apply the direct current as theseries of pulses having an average pulse duration of between 100milliseconds and 300 seconds.
 34. (canceled)
 35. The method according toclaim 32, wherein activating the control circuitry to drive theparenchymal and the ventricular electrodes comprises activating thecontrol unit to: drive the parenchymal and the ventricular electrodes toclear the substance by applying a voltage between the parenchymal andthe ventricular electrodes during each of the pulses, measure a currentresulting from application of voltage during each of the pulses, andterminate the pulse upon the measured current falling below a thresholdvalue.
 36. (canceled)
 37. The method according to claim 19, whereinimplanting the parenchymal and the ventricular electrodes comprisesimplanting the parenchymal and the ventricular electrodes such that anarea of build-up of the substance is between the parenchymal and theventricular electrodes. 38-40. (canceled)
 41. The method according toclaim 19, wherein implanting the parenchymal electrode comprisesimplanting the parenchymal electrode such that an area of build-up ofthe substance is between the parenchymal electrode and an area of theventricular system nearest the area of build-up. 42-44. (canceled) 45.The method according to claim 32, wherein activating the controlcircuitry to apply the direct current as the series of pulses comprisesactivating the control circuitry to set an average pulse duration of theseries of pulses to be at least 10 milliseconds.
 46. The apparatusaccording to claim 14, wherein the control circuitry is configured toset an average pulse duration of the series of pulses to be at least 10milliseconds.